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WO2002038153A1 - Nouvelle utilisation de derives de 4, 5, 6, 7-tetrahydroimidazo-[4,5-c]pyridine - Google Patents

Nouvelle utilisation de derives de 4, 5, 6, 7-tetrahydroimidazo-[4,5-c]pyridine Download PDF

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Publication number
WO2002038153A1
WO2002038153A1 PCT/SE2001/002523 SE0102523W WO0238153A1 WO 2002038153 A1 WO2002038153 A1 WO 2002038153A1 SE 0102523 W SE0102523 W SE 0102523W WO 0238153 A1 WO0238153 A1 WO 0238153A1
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Prior art keywords
imidazo
tetrahydro
rot
pyridine
mmol
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PCT/SE2001/002523
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English (en)
Inventor
Patrizia Caldirola
Olivier Besencon
Rolf Olsson
Johan ÖHMAN
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Biovitrum Ab
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Priority claimed from SE0004101A external-priority patent/SE0004101D0/xx
Application filed by Biovitrum Ab filed Critical Biovitrum Ab
Priority to AU2002214505A priority Critical patent/AU2002214505A1/en
Publication of WO2002038153A1 publication Critical patent/WO2002038153A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to use of 4-alkyl-5-alkoxycarbonyl-4, 5, 6, 7- tetrahydroimidazo[4,5-c] pyridine derivatives for the manufacture of medicaments for, or treatment or prophylaxis of semicarbazide-sensitive amine oxidase (SSAO)-mediated complications.
  • SSAO semicarbazide-sensitive amine oxidase
  • SSAO Semicarbazide-sensitive amine oxidase
  • IDDM insulin dependent diabetes mellitus
  • NIDDM non-insulin dependent diabetes mellitus
  • Heart attack, angina, strokes, amputations, blindness and renal failure are clinical events that represent the end point of the clinical study. Endothelial cells dysfunction may precede the diabetic state of complications.
  • the SSAO enzyme is located in the vascular smooth muscles, retina, kidney and the cartilage tissues, and in the circulating blood (Yu, P. H.
  • the general catalytic cycle is very similar to the one observed for other monoamine oxidases (Scheme 1).
  • the higher activity of SSAO as well as the higher concentration of its natural substrates, methylamine and aminoacetone, in diabetic patients, would lead to a higher production of formaldehyde, methylglyoxal and hydrogen peroxide.
  • These products are known to be highly cytotoxic for the endothelial cell layer and might lead to the observed microvascular complication in diabetic patients (Yu, P. H.
  • Scheme 1 SSAO's catalytic cycle.
  • the active site is represented schematically by the topaquinone residue as well as by a basic amino acid residue B " essential for the activity.
  • a method of treatment or prophylaxis of SSAO- mediated complications in mammals including humans comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of Formula (I):
  • R 5 is (a) H
  • C j .g alkyl denotes a saturated or unsaturated, straight, branched or cyclic alkyl group having from 1 to 8 carbon atoms.
  • Examples of said Cj.g alkyl include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, and straight- and branched-chain pentyl, hexyl, septyl and octyl, optionally substituted with 0-5 halogen atoms.
  • halogen shall mean fluorine, chlorine, or bromine.
  • Preferred compound of Formula (I) are: benzyl 4-methyl-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate; benzyl 4-ethyl-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate trifluoroacetate; benzyl 4-propyl-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate trifluoroacetate;
  • the compounds of the Formula (I) can form acid addition salts with acids such as conventional pharmaceutically acceptable acids, for example maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric and methanesulfonic .
  • acids such as conventional pharmaceutically acceptable acids, for example maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric and methanesulfonic .
  • Compounds of Formula (I) may also form solvates such as hydrates and the invention also extends to these forms. When referred to herein, it is understood that the term "compound of Formula (I)" also includes these forms.
  • Certain compounds of Formula (I) are capable of existing in stereoisomeric forms including diastereomers and enantiomers and the invention extends to each of these stereoisomeric forms and to mixtures thereof including racemates.
  • the different stereoisomeric forms may be separated one from the other by the usual methods. Any given isomer may be obtained by stereospecific or asymmetric synthesis.
  • the invention also extends to any tautomeric forms and mixtures thereof.
  • the compounds of Formula (I) are used for treatment or prophylaxis of SSAO mediated vascular complications and for insulin dependent diabetes mellitus and non-insulin dependent diabetes mellitus.
  • R H: Benzyl (4S,6S)-6-(aminocarbonyl)-4-et yl-
  • the starting materials are commercially available or can be prepared following known procedures.
  • the compounds for treatment of SSAO mediated complications can conveniently be administered in a pharmaceutical composition containing the compound in combination with a suitable excipient.
  • Such pharmaceutical compositions can be prepared by methods and contain excipients which are well known in the art. A generally recognized compendium of such methods and ingredients is Remington's Pharmaceutical Sciences by E.W. Martin (Mark Publ. Co., 15 th Ed., 1975).
  • the compounds and compositions can be administered orally, parenterally (for example, by intravenous, intraperitoneal or intramuscular injection), topically, or rectally.
  • Useful dosages of the compounds of Formula (I) can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known in the art; for example, see U.S. Pat. No. 4,938,949.
  • the compound can be administered in unit dosage form; for example, containing about 0.05 mg to about 500 mg, conveniently about 0.1 mg to about 250 mg, most conveniently, about 1 mg to about 150 mg of active ingredient per unit dosage form.
  • the desired dose may be presented in a single dose or as divided doses administered at appropriate intervals.
  • the compositions can be administered orally, sublingually, transdermally, or parenterally at dose levels of about 0.01 to about 150 mg kg, preferably about 0.1 to about 50 mg/kg, and more preferably about 0.1 to about 30 mg/kg of mammal body weight.
  • RP-HPLCs were run on a Gilson system, using a 119 UV-detector (214 nm or 254 nm), a 805 manometric module, a 305- and a 306-pumps and a Vydac C ⁇ 8 -column (218TP1022); H 2 O+0.1%TFA/CH 3 CN were used as eluents. Mps were measured with a Gallenkamp apparatus and were uncorrected. NMR spectra were recorded on a Varian Inova 400 instrument.
  • EI-MS spectra were recorded on a JMS SX-102A mass spectrometer (Jeol, Tokyo, Jpn) at 70eV or on an Autospec-oaTOF Micromass Manchester instrument at 70 eV.
  • HRMS spectra were recorded on a LCT Micromass instrument with flow injection-electrospray positive mode; quaternary ammonium salts were used as references. Reactions were followed by MS, using a Platform I Micromass instrument, Manchester, with an electrospray positive and negative mode flow injection. Elemental analysis was run on an Elementar Vario EL instrument.
  • Benzyl chloroformate (0.845 mL, 5.64 mmol) was added dropwise over 1 min. The pH was maintained between 7 and 9 by adding from time to time aq. IM NaOH (total amount: about 5 mL). The mixture was stirred overnight while the temperature rose slowly to room temperature. The final pH was equal to 6.5 and an oily precipitate was lying in the bottom of the flask. This oily precipitate was decanted, dissolved in CHC1 3 and the solution dried over MgSO . After filtration, the filtrate was evaporated under reduced pressure. The residue was diluted in MeOH (20 mL) and aq. IM NaOH was added (10 mL).
  • Example 6 Methyl 4-methyl-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5- carboxylate: According to GPII, starting from 4-methyl-4,5,6,7-tetrahydro-lH- imidazo[4,5-c]pyridine dihydrochloride (500 mg, 2.38 mmol), K 2 CO 3 (690 mg, 5.00 mmol), CHC1 3 (6 mL), H 2 O (3 mL) and methyl chloroformate (0.39 mL, 5.0 mmol). The reaction was carried out in a parallel fashion in a test-tube closed with a screwed tap and stirred in a Stew-stirrer.
  • Example 7 Benzyl 4-ethyl-l ,4,6,7-tetrahydro-5H-imidazo [4,5-c]pyridine-5-carboxylate trifluoroacetate: According to GPII, starting from 4-ethyl-4,5,6,7-tetrahydro-lH- imidazo[4,5-c]pyridine dihydrochloride (1.00 g, 4.48 mmol), K 2 CO 3 (1.24 g, 9.0 mmol), CHC1 3 (10 mL), H 2 O (8 mL) and benzyl chloroformate (1.36 mL, 9.0 mmol). After basic treatment for 1 h the mixture was acidified to pH 8-8.5 with aq. IM HCl.
  • Benzyl 4-phenyI-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5- carboxylate trifluoroacetate According to GPII, starting from 4-phenyl-4,5,6,7- tetrahydro-lH-imidazo[4,5-c]pyridine dihydrochloride (800 mg, 2.54 mmol), K 2 CO 3 (737 mg, 5.33 mmol), CHC1 3 (6 mL), H 2 O (5 mL) and benzyl chloroformate (0.80 mL, 5.33 mmol). After basic treatment for 1 h the mixture was acidified to pH 8 with aq. IM HCl.
  • Example 9 Benzyl 4-benzyl-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate: According to GPII, starting from 4-benzyl-4,5,6,7-tetrahydro-lH-imidazo[4,5- yridine dihydrochloride (500 mg, 1.74 mmol), K 2 CO 3 (507 mg, 3.67 mmol), CHC1 3 (6 mL), H 2 O (3 mL) and benzyl chloroformate (0.55 mL, 3.67 mmol). The reaction was carried out in a parallel fashion in a test-tube closed with a screwed tap and stirred in a Stew-stirrer.
  • Benzyl 4-propyl-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5- carboxylate trifluoroacetate According to GPII, starting from 4-propyl-4,5,6,7- tetrahydro-lH-imidazo[4,5-c]pyridine dihydrochloride (600 mg, 2.52 mmol), K 2 CO 3 (720 mg, 5.2 mmol), CHC1 3 (6 mL), H 2 O (5 mL) and benzyl chloroformate (0.78 mL, 5.2 mmol). After basic treatment for lh the mixture was acidified to pH 8.5 with aq. IM HCl.
  • Methyl 4-ethyl-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate trifluoroacetate According to GPII, starting from 4-ethyl-4,5,6,7-tetrahydro-lH- imidazo[4,5-c]pyridine dihydrochloride (600 mg, 2.68 mmol), K 2 CO 3 (778 mg, 5.63 mmol), CHC1 3 (6 mL), H 2 O (4 mL) and methyl chloroformate (0.436 mL, 5.63 mmol). After basic treatment for 1 h the mixture was acidified to pH 8 with aq. IM HCl.
  • Methyl 4-propyl-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5- carboxylate trifluoroacetate According to GPII, starting from 4-propyl-4,5,6,7- tetrahydro-lH-imidazo[4,5-c]pyridine dihydrochloride (600 mg, 2.52 mmol), K 2 CO 3 (720 mg, 5.2 mmol), CHC1 3 (6 mL), H 2 O (4 mL) and methyl chloroformate (0.40 mL, 5.2 mmol). After basic treatment for 1 h the mixture was acidified to pH 8-9 with aq. IM HCl.
  • Methyl 4-phenyl-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5- carboxylate trifluoroacetate According to GPII, starting from 4-phenyl-4,5,6,7- tetrahydro-lH-imidazo[4,5-c] pyridine dihydrochloride (800 mg, 2.54 mmol), K 2 CO 3 (737 mg, 5.33 mmol), CHC1 3 (8 mL), H 2 O (5 mL) and methyl chloroformate (0.412 mL, 5.33 mmol). After basic treatment for 1 h the mixture was acidified to pH 8 with aq. IM HCl.
  • Cyclopentyl 4-ethyl-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridme-5- carboxylate trifluoroacetate According to GPII, starting from 4-ethyl-4,5,6,7- tetrahydro-lH-imidazo[4,5-c]pyridine dihydrochloride (400 mg, 1.78 mmol), K 2 CO 3 (517 mg, 3.74 mmol), CHC1 3 (4 mL), H 2 O (2 mL) and cyclopentyl chloroformate (511 mg, 3.74 mmol). After basic treatment for 1 h the mixture was acidified to pH 9 with aq. IM HCl.
  • Example 18 Cyclopentyl 4-propyl-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5- carboxylate trifluoroacetate: According to GPII, starting from 4-propyl-4,5,6,7- tetrahydro-lH-imidazo[4,5-c]pyridine dihydrochloride (400 mg, 1.68 mmol), K 2 CO 3 (487 mg, 3.53 mmol), CHC1 3 (4 mL), H 2 O (2 mL) and cyclopentyl chloroformate (482 mg, 3.53 mmol). After basic treatment for 1 h the mixture was acidified to pH 8-9 with aq. IM HCl.
  • Cyclopentyl 4-phenyl-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5- carboxylate trifluoroacetate According to GPII, starting from 4-phenyl-4,5,6,7- tetrahydro-lH-imidazo[4,5-c]pyridine dihydrochloride (500 mg, 1.59 mmol), K 2 CO 3 (461 mg, 3.34 mmol), CHC1 3 (5 mL), H 2 O (2.5 mL) and cyclopentyl chloroformate (456 mg, 3.34 mmol). After basic treatment for 1 h the mixture was acidified to pH 8-9 with aq. IM HCl.
  • Example 21 4-Fluorophenyl 4-propyl-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5- carboxylate trifluoroacetate: According to GPII, starting from 4-propyl-4,5,6,7- tetrahydro-lH-imidazo[4,5-c]pyridine dihydrochloride (400 mg, 1.68 mmol), K 2 CO 3 (487 mg, 3.53 mmol), CHC1 3 (4 mL), H 2 O (2 mL) and 4-fluorophenyl chloroformate (0.47 mg, 3.6 mmol).
  • Methoxy-ethyI 4-ethyl-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5- carboxylate: According to GPII, starting from 4-ethyl-4,5,6,7-tetrahydro-lH- imidazo[4,5-c]pyridine dihydrochloride (400 mg, 1.78 mmol), K CO 3 (517 mg, 3.74 mmol), CHC1 3 (4 mL), H 2 O (2 mL) and methoxyethyl chloroformate (518 mg, 3.74 mmol). After basic treatment for 1 h the mixture was acidified to pH 9 with aq. IM HCl.
  • Methoxyethyl 4-propyl-l ,4,6,7-tetrahydro-5H-imidazo [4,5-c]pyridine-5- carboxylate According to GPII, starting from 4-propyl-4,5,6,7-tetrahydro-lH- imidazo[4,5-c]pyridine dihydrochloride (400 mg, 1.68 mmol), K 2 CO 3 (487 mg, 3.53 mmol), CHC1 3 (4 mL), H 2 O (2 mL) and methoxyethyl chloroformate (490 mg, 3.53 mmol). After basic treatment for 1 h the mixture was acidified to pH 8-9 with aq. IM HCl.
  • Methoxyethyl 4-phenyl-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5- carboxylate According to GPII, starting from 4-phenyl-4,5,6,7-tetrahydro-lH- imidazo[4,5-c]pyridine dihydrochloride (500 mg, 1.59 mmol), K 2 CO 3 (461 mg, 3.34 mmol), CHC1 3 (6 mL), H 2 O (4 mL) and methoxyethyl chloroformate (462 mg, 3.34 mmol). After basic treatment for 1 h the mixture was acidified to pH 8-9 with aq. IM HCl.
  • Benzyl 4-methyl-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5- carboxylate According to GPII, starting from 4-methyl-4,5,6,7-tetrahydro-lH- imidazo[4,5-c]pyridine dihydrochloride (500 mg, 2.38 mmol), K 2 CO 3 (690 mg, 5.00 mmol), CHC1 3 (6 mL), H 2 O (3 mL) and benzyl chloroformate (0.75 mL, 5.0 mmol). The reaction was carried out in a parallel fashion in a test-tube closed with a screwed tap and stirred in a Ste -stirrer.
  • Benzyl 4-benzyl-l ,4,6,7-tetrahydro-5H-imidazo [4,5-c]pyridine-5- carboxylate According to GPII, starting from 4-benzyl-4,5,6,7-tetrahydro-lH- imidazo[4,5-c]pyridine dihydrochloride (500 mg, 1.74 mmol), K 2 CO 3 (507 mg, 3.67 mmol), CHC1 3 (6 mL), H 2 O (3 mL) and benzyl chloroformate (0.55 mL, 3.67 mmol). The reaction was carried out in a parallel fashion in a test-tube closed with a screwed tap and stirred in a Ste ⁇ n-stirrer.
  • the reaction was carried out in a parallel fashion in a test-tube closed with a screwed tap and stirred in a Stem-stirrer.
  • the basic treatment was carried out in MeOH (6 mL) and aq. IM NaOH (4 mL). After 1 h the mixture was acidified with aq. IM HCl (3 mL). The reaction mixture was evaporated in a speed-vac overnight. The residue was triturated with CHC1 3 and filtered several times. The combined org. phases were evaporated in a speed- vac.
  • the residue was purified by parallel FC with a gradient pump (MeOH/CHCl 3 0:100 -> 0:100 for 5 min, then -> 15:85 over 25 min).
  • 5-carboxylate According to GPII, starting from 4-ethyl-4,5,6,7-tetrahydro-lH- imidazo[4,5-c]pyridine dihydrochloride (500 mg, 2.23 mmol), K 2 CO 3 (646 mg, 4.68 mmol), CHC1 3 (6 mL), H 2 O (3 mL) and 2,2,2-trichloroethyl chloroformate (0.64 mL, 4.68 mmol). The reaction was carried out in a parallel fashion in a test-tube closed with a screwed tap and stirred in a Stem-stirrer. The basic treatment was carried out in MeOH (6 mL) and aq. IM NaOH (4 mL).
  • 2,2,2-Trichloroethyl -4-propy 1-1 ,4,6,7-tetrahy dro-5H-imidazo [4,5- c]pyridine-5-carboxylate According to GPII, starting from 4-propyl-4,5,6,7- tetrahydro-lH-imidazo[4,5-c]pyridine dihydrochloride (500 mg, 2.10 mmol), K 2 CO 3 (609 mg, 4.40 mmol), CHC1 3 (6 mL), H 2 O (3 mL) and 2,2,2-trichloroethyl chloroformate (0.61 mL, 4.4 mmol).
  • the reaction was carried out in a parallel fashion in a test-tube closed with a screwed tap and stirred in a Stew-stirrer.
  • the basic treatment was carried out in MeOH (6 mL) and aq. IM NaOH (4 mL). After 1 h the mixture was acidified with aq. IM HCl (3 mL). The reaction mixture was evaporated in a speed-vac overnight. The residue was triturated with CHC1 3 and filtered several times. The combined org. phases were evaporated in a speed-vac.
  • the residue was purified by parallel FC with a gradient pump (MeOH/CHCl 3 0:100 ⁇ 0:100 for 5 min, then ⁇ 15:85 over 25 min).
  • 2,2,2-Trichloroethyl -4-propyl-l ,4,6,7-tetrahydro-5H-imidazo [4,5- c]pyridine-5-carboxylate According to GPII, starting from 4-propyl-4,5,6,7- tetrahydro-lH-imidazo[4,5-c]pyridine dihydrochloride (500 mg, 2.10 mmol), K 2 CO 3 (609 mg, 4.40 mmol), CHC1 3 (6 mL), H 2 O (3 mL) and 2,2,2-trichloroethyl chloroformate (0.61 mL, 4.4 mmol).
  • the reaction was carried out in a parallel fashion in a test-tube closed with a screwed tap and stirred in a Stem-stirrer.
  • the basic treatment was carried out in MeOH (6 mL) and aq. IM NaOH (4 mL). After 1 h the mixture was acidified with aq. IM HCl (3 mL). The reaction mixture was evaporated in a speed- vac overnight. The residue was triturated with CHC1 3 and filtered several times. The combined org. phases were evaporated in a speed-vac.
  • the residue was purified by parallel FC with a gradient pump (MeOH/CHCl 3 0:100 ⁇ 0:100 for 5 min, then ⁇ 15:85 over 25 min).
  • the reaction was carried out in a parallel fashion in a test-tube closed with a screwed tap and stirred in a Stem-stirrer.
  • the basic treatment was carried out in MeOH (6 mL) and aq. IM NaOH (4 mL). After 1 h the mixture was acidified with aq. IM HCl (3 mL). The reaction mixture was evaporated in a speed-vac overnight. The residue was triturated with CHC1 3 and filtered several times. The combined org. phases were evaporated in a speed- vac.
  • Example 37 o 5-(4-Nitrob enzyl)-4-propyl-l ,4,6,7-tetrahy dro-5H-imidazo [4,5-c] py ridine-5- carboxylate: According to GPII, starting from 4-propyl-4,5,6,7-tetrahydro-lH- imidazo[4,5-c]pyridine dihydrochloride (500 mg, 2.10 mmol), K 2 CO 3 (609 mg, 4.40 mmol), CHC1 3 (6 mL), H 2 O (3 mL) and old 4-nitrophenyl chloroformate (949 mg, 4.40 mmol).
  • This method is based on the horseradish peroxidase catalyzed hydrogen peroxide oxidation of 10-acetyl-3,7-dihydroxyphenoxazine (Molecular Probes A-6550), that yields a highly fluorescent product, resorufin.
  • 10 mM stock solution of substance in DMSO is serially diluted in 0.05 M sodium-potassium phosphate buffer.
  • SSAO substrate benzylamine
  • HRP horse radish peroxidase
  • the final concentrations in the assay volume are 104 ⁇ M benzylamine, 219 ⁇ M 10-acetyl-3,7-dihydroxyphenoxazine, 1.1 U/ml HRP and a dilution of the SSAO preparation of 1/600.
  • the fluorescence is measured at 560 ex / 590 em.
  • the inhibition is measured as % decrease of the signal compared to a control containing dilution of DMSO only (no substance).
  • Aldehyde detection SSAO activity is measured as increase of aldehyde formed from SSAO degradation of primary amines.
  • 14 C -labeled benzylamine is mixed with substance dilutions (from 10 mM stock solution in DMSO) in 0.05 M sodium-potassium phosphate buffer (pH 7.8). Enzyme, also diluted in phosphate buffer, is added and incubation is performed at room temperature for 60 minutes. The reaction is stopped with 1 M HCl. The formed ( 1 C -labeled) aldehyde is separated from the likewise 14 C -labeled benzylamine through extraction with toluene:ethyl acetate and then transferred to liquid scintillation vials for measurement of radioactivity in a beta counter.
  • the final concentrations in the assay volume are 150 ⁇ M benzylamine (0.037 MBq/ ⁇ mol), and a dilution of the SSAO preparation of l/150.
  • the inhibition is measured as % decrease of the signal compared to control containing dilution of DMSO only (no substance).
  • the compounds shown in Tables 2 and 3 were tested for biological activity, determined as per cent inhibition of SSAO at 12 ⁇ M concentration of the test compounds. The compounds were shown to inhibit SSAO to from 10 to 97 %.

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Abstract

L'invention concerne l'utilisation de composés représentés par la formule (I), dans laquelle R?1, R2, R3 et R4¿ sont tels que spécifiés dans la description, pour le traitement ou la prévention de complications à médiation de SSAO, telles que le diabète.
PCT/SE2001/002523 2000-11-09 2001-11-09 Nouvelle utilisation de derives de 4, 5, 6, 7-tetrahydroimidazo-[4,5-c]pyridine WO2002038153A1 (fr)

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